US veterans have higher prevalence rates than the general population for Alcohol Use Disorders (AUD) and binge drinking. This project has established several genetic animal models for aspects of AUD. We are employing a mouse model of binge-like drinking to intoxication to study the risks for and consequences of such binge-like drinking on networks of brain genes. Using transcriptional data from a genetic screen of nave High Drinking in the Dark (HDID) mice, we identified as a druggable target the extracellular matrix (ECM). We will investigate drugs that affect the ECM for efficacy to reduce binge-like drinking. We will combine studies of the brain pathways of binge drinking with genome analyses to identify novel drugs that will be tested to see whether they can prevent withdrawal-induced escalated drinking. Specifically, we will determine the transcriptional changes associated with withdrawal-escalated consumption in HDID mice of both sexes. We will use transcriptional data from two brain areas, nucleus accumbens shell (NAS) and the lateral orbital frontal cortex (LOC), both known to be associated with binge consumption, to screen databases to find compounds that can be tested for possible reduction of withdrawal-escalated consumption. After 6 weeks of drinking in the dark (a binge-like procedure, DID), mice will be exposed to 6 repeated cycles of intermittent ethanol vapor inhalation followed by access to drinking, or only to air. After completion of this protocol, drinking will have escalated and brains will be harvested for laser microcapture of NAS and LOC. RNA-Seq will be performed on these tissues to obtain transcriptional data. Network-centric analyses will identify key hub nodes and/or pathways that can be targeted for manipulation by compounds nominated by database searches (e.g., the Library of Integrated Network-Based Cellular Signatures: LINCS). We will then determine whether a nominated compound is effective in reducing post-escalation drinking. We have nearly 40 years experience with vapor inhalation and our detailed methodology for chronic intermittent vapor inhalation and withdrawal have been published. We have also published data showing increased drinking by HDID mice after repeated withdrawal episodes using the chronic intermittent exposure (CIE) vapor inhalation model.